Triple negative breast cancer (TNBC) has a poor prognosis and, by definition, lacks estrogen receptor and progesterone receptor expression as well as HER2 amplification and thus is unresponsive to targeted HER2 or endocrine therapy. Although TNBC lacks expression of hormone receptors commonly associated with breast cancer, androgen receptor (AR) protein is expressed in 12-32% of TNBC. AR is a well characterized driver of prostate cancer that is effectively targeted with FDA-approved antagonists. The goal of the proposed study is to determine the function of AR in TNBC and whether AR antagonists used to treat prostate cancer may be effective in AR+ TNBC. Based on the preliminary data outlined in this proposal, we have generated a working model of AR action in TNBC in which AR acts as a transcription factor to regulate key genes, including amphiregulin (AREG). Transcription of these genes allows AR to mediate proliferation, migration and invasion and maintain a cancer stem cell (CSC) population. We hypothesize that inhibiting AR will prevent these functions and impede tumor growth and invasion. The aims of this proposal are to determine how AR influences proliferation, invasion and cancer stem cell maintenance (Aim 1) and to determine if AR inhibition will decrease tumor growth, initiation and metastasis in preclinical animal models (Aim 2). In Aim 1, the mechanism of AR function in TNBC will be determined by assessing transcriptional regulation of critical genes, performing phenotype rescue experiments and evaluating CSC populations. Aim 2 will be assessed using TNBC xenograft models treated with an AR antagonist. Completion of the proposed studies will determine if and how AR supports tumor progression in AR+ TNBC and guide the rational use of anti-androgen therapy to improve patient outcome. Together, these studies will serve to guide the development of a new, molecularly- targeted therapy in this aggressive breast cancer subtype with limited therapeutic options.